Abstract

Diabetes is a negative risk factor for aortic aneurysm, but the underlying explanation for this phenomenon is unknown. We have previously demonstrated that Cell Division Autoantigen 1 (CDA1), which enhances TGF-β signaling, is upregulated in diabetes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wildtype, CDA1 knockout, Apolipoprotein E (ApoE) knockout and CDA1/ApoE double knockout (dKO) mice were rendered diabetic. Whereas aneurysms were not observed in diabetic ApoE knockout and wildtype mice, 40% of diabetic dKO mice developed aortic aneurysms. These aneurysms were associated with attenuated aortic TGF-β signaling, reduced expression of various collagens as well as increased aortic macrophage infiltration and matrix metalloproteinase12 expression. In the well characterized model of angiotensin II (AngII) induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated suprarenal aortic expansion, changes not seen in dKO mice. Furthermore, aortic CDA1 expression was downregulated ∼70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 deletion in diabetic mice promotes aneurysm formation provides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.